Rhodium-Catalyzed [5+2] Cycloaddition of 3-Acyloxy-1,4-enyne with Alkene or Allene

Article abstract of DOI:10.1002/adsc.201600196

We recently developed a completely new type of Rh-catalyzed [5+2] cycloaddition by using 3-acyloxy-1,4-enyne (ACE) as the 5-carbon building block. In this update, we show that ACE can undergo intramolecular [5+2] cycloaddition with either an alkene or an allene in the presence of an appropriate rhodium catalyst and ligands to afford bicyclic compounds with multiple stereogenic centers. In most cases, cis-fused bicyclo[5.3.0]decadienes are prepared highly diastereoselectively. (Figure presented.) .

Full text of DOI:10.1002/adsc.201600196

UPDATES
DOI: 10.1002/adsc.201600196
Rhodium-Catalyzed [5+2] Cycloaddition of 3-Acyloxy-1,4-enyne
with Alkene or Allene
a
a
a
a,b,
Wangze Song, John C. Lynch, Xing-zhong Shu, and Weiping Tang *
a
School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA
Fax: (+1)-608-262-5345; phone: (+1)-608-890-1846; e-mail: wtang@pharmacy.wisc.edu
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53705, USA
b
Received: February 16, 2016; Revised: April 5, 2016; Published online: May 24, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600196.
Abstract: We recently developed a completely new
type of Rh-catalyzed [5+2] cycloaddition by using
ring systems by forming at least two bonds during the
ring-forming event. Numerous cycloaddition reactions
have been developed for the synthesis of four-, five-,
and six-membered rings. For example, Diels–Alder
cycloaddition is one of the most widely used methods
for the stereoselective synthesis of six-membered
rings with multiple stereogenic centers. In contrast,
a cycloaddition that can match the scope and stereo-
control of Diels–Alder cycloaddition for the synthesis
of seven-membered rings, the homolog of Diels–
Alder cycloaddition, has yet to be discovered, al-
though the seven-membered ring is as prevalent as
five- and six-membered rings in natural products.
Among the three types of two-component cycload-
ditions including [6+1], [5+2], and [4+3], the [5+2]
cycloaddition is particularly attractive because a varie-
ty of two-carbon components are readily available,
3
-acyloxy-1,4-enyne (ACE) as the 5-carbon building
block. In this update, we show that ACE can under-
go intramolecular [5+2] cycloaddition with either
an alkene or an allene in the presence of an appro-
priate rhodium catalyst and ligands to afford bicy-
clic compounds with multiple stereogenic centers.
In most cases, cis-fused bicyclo[5.3.0]decadienes are
prepared highly diastereoselectively.
Keywords: allenes; catalysis; cycloaddition; enynes;
rhodium
The bicyclo[5.3.0]decane carbon skeleton is present in such as alkynes, alkenes, and allenes. The discovery of
numerous bioactive sesquiterpenes and diterpenes as novel five-carbon building blocks is highly desirable
[
1]
shown in Figure 1. The importance of this bicyclic and will lead to a plethora of new [5+2] cycloaddi-
structure continues to stimulate the development of tions. Most [5+2] cycloadditions reported to date
[
2]
[3]
novel and efficient stereoselective methods. Cyclo- used vinylcyclopropanes or related species such as
[4]
[5]
addition is one of the most efficient ways to access iminylcyclopropanes,
allenylcyclopropanes,
epoxides, and vinylaziridines, as the five-carbon
component. In 2011, we first reported that 3-acyloxy-
vinyl
[6]
[7]
1
,4-enyne (ACE) could serve as a novel 5-carbon
component for Rh-catalyzed [5+2] cycloaddition with
alkynes for the synthesis of cycloheptatrienes
[8]
(
Scheme 1). Cycloadditions with less reactive al-
kenes are generally much more challenging than
those with alkynes. Cycloaddition products derived
from alkenes, however, are also more attractive be-
cause multiple stereogeneric centers can be generated
in a single step. We found that alkene could partici-
pate in the Rh-catalyzed intramolecular [5+2] cyclo-
addition with ACE and communicated this result re-
[9]
cently. In this update, we further explored the scope
of the Rh-catalyzed intramolecular [5+2] cycloaddi-
tion of ACE with alkenes and describe the intramo-
lecular [5+2] cycloaddition of ACE with allenes for
Figure 1. Carbon skeletons of selected terpene families.
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Scheme 1. ACE as the 5-carbon building block for Rh-cata-
lyzed [5+2] cycloadditions.
[
10]
the first time. In all [5+2] cycloadditions involving
ACEs, a 1,2-acyloxy migration also occurred.
[
9]
Various substrates 1a were prepared by adopting
[8]
our previously established procedures (Scheme 2).
We found that the cationic rhodium catalyst did not
provide any desired cycloaddition product, while
a neutral rhodium catalyst with electron-deficient
phosphine or phosphite ligands generally afforded 2a
[
9]
in good yields. The combination of [Rh(coe) Cl]
2
2
and [3,5-(CF ) C H ] P worked for various substrates
3
2
6
3 3
[
9]
with different linker X and ester R units. The chiral-
ity in the substrates could be transferred to the prod-
ucts.
We have previously shown that ACEs with an inter-
nal alkyne tend to undergo 1,3-acyloxy migration to
[
8,11]
form allene intermediates.
For Rh-catalyzed [5+2]
Scheme 2. Scope of Rh(I)-catalyzed intramolecular [5+2]
cycloaddition of ACE with alkene.
cycloaddition of ACEs with alkynes, electron-with-
drawing groups including ester, ketone and bromine
on the terminal position of alkyne can switch the re-
gioselectivity back to 1,2-acyloxy migration and pro-
[8]
mote the formation of [5+2] cycloaddition products.
observe an obvious difference between substrates 1d
ACEs in substrates 1b could also undergo Rh-cata- and 1f.
lyzed [5+2] cycloaddition with the tethered alkene to No desired product was obtained for substrate 1g
with an ester linkage. Efforts towards the synthesis of
[
9]
yield products 2b successfully.
In addition to monosubstituted alkene, we also in- a tricyclic product were also not successful when an
vestigated polysubstituted alkenes in the [5+2] cyclo- enol ether was employed as the 2-carbon component
addition of ACE with alkene. Alkyl groups could not in 1h. We also tried substrate 1i with a six-carbon
be tolerated on either the internal or external posi- tether. Less than 20% yield of product was observed
tion. Various aryl groups could be tolerated in sub- by NMR. Pure product could not be isolated under
[
9]
strates 1c with a gem-diester linker. We now demon- standard conditions.
strate that substrate 1d with a sulfonamide tether and
We next prepared substrate 3a to examine the pos-
substrate 1e with a bromine substituent are also com- sibility of Rh-catalyzed intramolecular [5+2] cycload-
patible with phenyl-substituted alkene to afford prod- dition of ACE with allenes. No reaction occurred by
ucts 2d and 2e, respectively.
using Wilkinsonꢁs catalyst (entry 1, Table 1). A com-
Previously, we found that the yields of [5+2] cyclo- plex mixture was observed when the catalyst was
addition products could be slightly increased by switched to [Rh(cod)OH] (entry 2). A cationic cata-
2
around 5% when the pivalate was replaced by elec- lyst afforded the desired cycloaddition product 4a,
[
9]
tron-rich para-dimethylaminobenzoate. We did not albeit in low yield (entry 3). The addition of different
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Table 1. Screening of catalysts and conditions for intramolecular [5+2] cycloaddition of ACE and allene.
[
a]
Entry
Conditions
Yield
NR
1
2
3
4
5
6
7
8
9
Rh(PPh ) Cl (5 mol%), DCE, 808C
3
3
[Rh(cod)OH] (5 mol%), DCE, 8 h, 808C
complex
30%
2
[Rh(cod) ]BF (5 mol%), DCE, 8 h, r.t. or 808C
2
4
[Rh(cod) ]BF (5 mol%), DCE, 8 h, [(CF ) CHO] P (30 mol%), 808C
NR
2
4
3
2
3
[Rh(cod) ]BF (5 mol%), DCE, 8 h, [CF CH O] P (30 mol%), 808C
complex
33%
2
4
3
2
3
[Rh(cod) ]BF (5 mol%), DCE, 8 h, [3,5-(CF ) C H ] P (30 mol%), 808C
2
4
3
2
6
3 3
[Rh(cod)Cl] (5 mol%), DCE, [3,5-(CF ) C H ] P (30 mol%), 808C
[Rh(cod)Cl] (5 mol%), CHCl , [3,5-(CF ) C H ] P (30 mol%), 608C
[Rh(cod)Cl] (5 mol%), CH Cl , [3,5-(CF ) C H ] P (30 mol%), 408C
41%
20%
33%
2
3
2
6
3 3
2
3
3
2
6
3 3
2
2
2
3
2
6
3 3
1
1
1
1
1
1
0
1
2
3
4
5
[Rh(coe) Cl] (5 mol%), DCE, [3,5-(CF ) C H ] P (30 mol%), 808C
46%
55% (52%)
34%
25%
NR
2
2
3
2
6
3 3
[b]
[Rh(coe) Cl] (5 mol%), DCE, [3,5-(CF ) C H ] P (30 mol%), 908C
2
2
3
2
6
3 3
[Rh(coe) Cl] (5 mol%), DCE, [3,5-(CF ) C H ] P (30 mol%), 1108C
2
2
3
2
6
3 3
[Rh(coe) Cl] (5 mol%), DCE, (p-CF C H ) P (30 mol%), 908C
2
2
3
6
4 3
[Rh(coe) Cl] (5 mol%), DCE, [CF CH O] P (30 mol%), 908C
2
2
3
2
3
[Rh(coe) Cl] (5 mol%), DCE, (C F ) P (30 mol%), 908C
NR
2
2
6 5 3
[
[
a]
1
Yields were calculated based on H NMR using internal standard.
b]
Isolated yield; NR=no reaction, DCE=dichloroethane, cod=cyclooctadiene, coe=cyclooctene.
electron-poor phosphite ligands led to either no reac- often the minor component in the crude products. It
tion or a complex mixture (entries 4 and 5). The addi- was not clear to us why diene 4e’ became the major
tion of an electron-poor phosphine ligand to the cat- product. The diene products were likely generated by
ionic rhodium catalyst led to a 33% yield of product allylic CÀH activation to form Rh-p-allyl followed by
[12]
4a (entry 6). The addition of the same ligand to b-hydride elimination.
[
Rh(cod)Cl] led to a slightly improved yield of 4a
We were also surprised that substrate 3f failed to
2
(
entry 7). No further improvement was observed by afford the desired cycloaddition product and only
examining different solvents (entries 8 and 9). Re- a complex mixture was obtained (entry 5). An inter-
placement of the [Rh(cod)Cl]2 catalyst by nal alkyne with a bromine substituent could be toler-
[
(
Rh(coe) Cl] further improved the yield to 46% ated in the ACE moiety (entry 6).
2 2
entry 10). A 52% isolated yield was obtained by rais-
We also introduced a gem-dimethyl group to the
ing the temperature to 908C (entry 11). A lower yield carbon adjacent to ACE in substrates 3h and 3i, with
was obtained after further raising the temperature an oxygen and tosylamide linker, respectively (en-
(
entry 12). Other combinations of metal precursor tries 7 and 8). While product 4h with a cis-configura-
and ligands did not improve the yield. One major by- tion was isolated in 56% yield, both cis- and trans-
product observed on the NMR of the crude product products 4i and 4i’ were isolated. The major isomer 4i
was the diene isomer derived from allene. This was had the cis-configuration, which was assigned based
unambiguously confirmed later by isolating the diene on nOe studies. The gem-dimethyl group in the linker
by-product derived from a substrate in Table 2.
region clearly influenced the conformation of the sub-
After extensive screening of different conditions, strate during its coordination to the metal catalyst
we were not able to improve the yield of the cycload- and led to the formation of trans-product.
dition product further for allenes. We began to ex-
Based on the mechanism previously proposed for
plore the scope of the substrates (Table 2). Substrate Rh-catalyzed [5+2] cycloaddition of ACEs and alk-
[8d]
3
b with an electron-rich dimethylaminobenzoate ester ynes, the mechanisms for the Rh-catalyzed intramo-
provided a slightly higher yield of the product than 3a lecular [5+2] cycloadditions with alkenes or allenes
entry 1). This was also true for substrates with an are proposed in Scheme 3. Oxidative cyclization of
oxygen tether (entries 2 and 3). Interestingly, diene metal complexes 5 and 9 accompanied by 1,2-acyloxy
e’ was obtained as the major product when para-me- migration yield metallacycles 6 and 10, respectively.
(
4
thoxybenzoate was employed as the ester (entry 4). Insertion of the tethered alkene or allene to these
Diene by-products were also observed in the NMR of two metallacycles affords intermediates 7 and 11, re-
the crude products in all other cases. But they were spectively. Finally, products 8 and 12 are formed after
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Table 2. Scope of Rh(I)-catalyzed intramolecular [5+2] cy-
[a]
cloaddition of ACE with allene.
[
b]
Entry Substrate
Product
Yield
1
3b (R=p-
4b
58%
Me NC H )
2
6
4
2
3
3c (R=t-Bu)
3d (R=p-
4c
4d
45%
55%
Me NC H )
2
6
4
4
3e (R=p-MeOC H )
58%
6
4
–
Scheme 3. Proposed mechanism for Rh(I)-catalyzed intra-
molecular [5+2] cycloaddition of ACE and alkene or allene.
5
6
3f (E=CO Me)
complex
50%
2
derived from these two new [5+2] cycloadditions
have one or two more stereogenic centers compared
to the previously reported [5+2] cycloaddition of
ACE and alkynes. High diastereoselectivity could be
achieved in most cases. For the intramolecular [5+2]
cycloaddition of ACE and allene, the reaction oc-
curred preferentially for the internal alkene.
3g
3h
4g
4h
7
8
56%
58%
Experimental Section
General Procedure for the [5+2] Cycloaddition of
ACE with Alkene
To a solution of [Rh(coe) Cl] (3.6 mg, 5 mol%) in 1,2-di-
2
2
chloroethane (1 mL) at room temperature was added
tris[3,5-bis(trifluoromethyl)phenyl]phosphine (20 mg,
0 mol%) under an argon atmosphere. The reaction solution
10%
3
was stirred at room temperature for 10 min. The alkene sub-
strate (0.1 mmol) was added. The reaction mixture was al-
lowed to stir at 808C for 20 h. The solvent was removed
under reduced pressure and the residue was purified by
column chromatography on silica gel to afford the corre-
sponding bicyclic product.
[
[
a]
Conditions: [Rh(coe) Cl]2 (5 mol%), [3,5-(CF ) C H ] P
2
3
2
6
3 3
(30 mol%), DCE, 908C, 6–12 h.
b]
All yields were isolated yields.
reductive elimination of the two eight-membered
metallacycles.
General Procedure for the [5+2] Cycloaddition of
ACE with Allene
In conclusion, we have developed Rh-catalyzed
[
5+2] cycloadditions of ACEs with a tethered alkene
To a solution of [Rh(coe) Cl] (3.6 mg, 5 mol%) in 1,2-di-
2
2
or a tethered allene for the synthesis of highly func- chloroethane (1 mL) at room temperature was added
tionalized bicyclic 5–7 fused ring systems. Products tris[3,5-bis(trifluoromethyl)phenyl]phosphine
(20 mg,
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3
0 mol%) under an argon atmosphere. The reaction solution
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was stirred at room temperature for 10 min. The allene sub-
strate (0.1 mmol) was added. The reaction mixture was al-
lowed to stir at 908C for 6–12 h. The solvent was removed
under reduced pressure and the residue was purified by
column chromatography on silica gel to afford the corre-
sponding bicyclic product.
[
[
Acknowledgements
5] F. Inagaki, K. Sugikubo, Y. Miyashita, C. Mukai,
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We thanks University of Wisconsin-Madison and NSF
2010, 49, 2206.
(CHE-1464754) for funding. This study made use of the Me-
[
[
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